DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1048
Inflammatory stimuli
e.g. IL-1β, TNF-α
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
NF-κB p65
p50
κB
Inflammatory genes
Cytokines, chemokines,
adhesion molecules,
inflammatory receptors,
enzymes, proteins
IKKβ
p50
p65
CBP
HAT
Acetylation
Gene
transcription
GR
–
HDAC2
Gene
repression
Corticosteroid
GR
Deacetylation
Cytoplasm
Nucleus
Figure 36–9. Mechanism of anti-inflammatory action of corticosteroids in asthma. Inflammatory genes are activated by inflammatory
stimuli (IL-1, TNF-, etc.), resulting in activation of IKK (inhibitor of I-B kinase-), which activates the transcription factor
nuclear factor B (NF-B). A dimer of p50 and p65 NF-B proteins translocates to the nucleus and binds to specific B recognition
sites and also to coactivators, such as CREB-binding protein (CBP), which have intrinsic histone acetyltransferase (HAT) activity. This
results in acetylation of core histones and consequent increased expression of genes encoding multiple inflammatory proteins. Cytosolic
glucocorticoid receptors (GR) bind corticosteroids; the receptor-ligand complexes translocate to the nucleus and bind to coactivators
to inhibit HAT activity in two ways: directly and, more importantly, by recruiting histone deacetylase-2 (HDAC2), which reverses histone
acetylation, leading to the suppression of activated inflammatory genes.
Steroids potently inhibit the formation of cytokines (e.g., IL-1,
IL-3, IL-4, IL-5, IL-9, IL-13, TNF-, and granulocyte-macrophage
colony-stimulating factor, GM-CSF) that are secreted in asthma by
T-lymphocytes, macrophages, and mast cells. Corticosteroids also
decrease eosinophil survival by inducing apoptosis. Corticosteroids
inhibit the expression of multiple inflammatory genes in airway
epithelial cells, probably the most important action of ICS in suppressing
asthmatic inflammation. Corticosteroids also prevent and
reverse the increase in vascular permeability due to inflammatory
mediators in animal studies and may therefore lead to resolution of
airway edema. Steroids have a direct inhibitory effect on mucus glycoprotein
secretion from airway submucosal glands, as well as indirect
inhibitory effects by down-regulation of inflammatory stimuli
that stimulate mucus secretion.
Corticosteroids have no direct effect on contractile responses
of airway smooth muscle; improvement in lung function after ICS is
presumably due to an effect on the chronic airway inflammation and
airway hyperresponsiveness. A single dose of ICS has no effect on
the early response to allergen (reflecting their lack of effect on mast
cell mediator release) but inhibits the late response (which may be
due to an effect on macrophages, eosinophils, and airway wall
edema) and also inhibits the increase in airway hyperresponsiveness.
ICS have rapid anti-inflammatory effects, reducing airway
hyperresponsiveness and inflammatory mediator concentrations in
sputum within a few hours (Erin et al., 2008). However, it may take
several weeks or months to achieve maximal effects on airway
hyperresponsiveness, presumably reflecting the slow healing of
the damaged inflamed airway. It is important to recognize that